Dr. Peris is currently an Assistant Professor in the College of Pharmacy at the University of Florida. Her primary research interest is studying the neurochemical basis for behavioral changes, including increases in seizure sensitivity, induced by different chronic drug exposure. She is pursuing this interest in her current R01 grant from NIAAA and is planning future grant proposals along these same lines. The research project described in this proposal will study changes in nigrostriatal and nigrotectal GABAergic neurotransmission that occur with increased seizure sensitivity. The GABAergic striatonigral and nigrotectal pathways appear to play a major role in the control of seizure activity but it is not known if these inhibitory GABAergic pathways are affected similarly by different proconvulsant treatments. Parameters of GABAergic transmission include GABA release, GABA(A) receptor binding and GABA(A) receptor-mediated Cl- flux. These measures will be made in substantia nigra (SN), superior colliculus (SC) and inferior colliculus (IC) in three proconvulsant models that have opposite initial effects on GABA(A) receptor function. The first model of increased seizure susceptibility will use rats chemically kindled with the benzodiazepine inverse agonist, FG7142, which suppresses GABA(A) receptor function. The second model will use alcohol-withdrawn rats with increased susceptibility to handling-induced seizures. Ethanol enhances GABA(A) receptor function. The third model will use rats kindled via repeated electrical stimulation of the amygdala which does not directly affect GABA systems. It is proposed that after each of these proconvulsant treatments, GABA function will decrease in the striatonigral pathway and increase in the nigrotectal pathway and that these changes are not dependent on the occurrence of a seizure. This pattern of changes would greatly increase inhibitory output to the SC, thereby decreasing SC output to reticular formation and spinal cord which and increasing seizure susceptibility. If a similar pattern of changes occurs in GABAergic transmission in the striatonigral and nigrotectal pathways in each of these three models, then a more general role of these GABAergic pathways is indicated. These studies will have important implications in the characterization and potential treatment of seizures. Dr. Peris' future projects include eventual renewal of the R01 described above plus another research proposal to ADAMHA on the neurochemical changes in GABA and dopamine transmission during chronic concurrent ethanol and cocaine exposure. The University of Florida Health Sciences Center has a strong program in the study of alcohol and drug abuse, including faculty in Dr. Peris' department and in the Departments of Pharmacology and Neuroscience in the College of Medicine. This is therefore a strong, supportive environment in which the candidate can interact with more senior faculty. This RSDA will give the candidate the financial support necessary to pursue her research interest as her sole focus in the next 5 years, and to develop her own strong, independent research program.